Pirlimycin adenylate (U-63,440) is a clindamycin analog possessing antiarrhythmic activity. In the anesthetized dog, the sustained ventricular tachycardia produced by ouabain intoxication is converted to a normal sinus rhythm with an average dose of 26.0 +/- 5.1 mg/kg of pirlimycin adenylate (range 13.4-40.7 mg/kg i.v.). The drug failed, however, to decrease arrhythmia frequency in a modified 2-day Harris dog preparation even with doses of up to 100 mg/kg. The efficacy of pirlimycin adenylate against ouabain-induced arrhythmias cannot be ascribed to a local anesthetic action, since concentrations of up to 5 X 10(-3) M produced only a small (26 +/- 5%) reduction in the spike amplitude of desheathed isolated frog sciatic nerves. In contrast, lidocaine (5 X 10(-3) M) produced a 91% reduction in single spike amplitude. Neither did pirlimycin adenylate (up to 10(-3) M) produce any negative inotropic effect in isolated cat papillary muscles, while both lidocaine and quinidine were cardiodepressant at 10(-3) M. It is concluded that pirlimycin adenylate may be an interesting prototype antiarrhythmic agent and further chemical modification of the drug molecule might increase the spectrum of antiarrhythmic activity without altering the drug's toxicity.